1. Field of the Invention
This invention is directed to therapeutic medical devices and methods of making and using the same.
2. Description of the State of the Art
Burns are one of the most common and devastating forms of trauma (reviewed in Church et al.)5. Data from the U.S. National Center for Injury Prevention and Control show that approximately 2 million fires are reported each year which result in 1.2 million people with burn injuries5. Moderate to severe burn injuries requiring hospitalization account for approximately 100,000 of these cases, and about 5,000 patients die each year from burn related complications5. Annual burn care costs in the United States exceeds US$18 billion dollars5.
When significantly injured, the skin's ability to fight infection, maintain fluid balance, and regulate temperature is compromised until skin integrity is restored6. A major burn is defined as >25-30% total body surface area (TBSA) partial burn (2nd degree) and full-thickness burn (3rd degree) or >10% full-thickness burn7. Burns are further broken down into 3 distinctive zones: coagulation, stasis, and hyperemia8. The zone of coagulation/necrosis forms the nonviable burn eschar nearest to the heat source8. The zone of stasis surrounds the central necrosis area and comprises tissue that is initially viable but, due to hypoperfusion and ischemia, may die and join the zone of coagulation/necrosis. Thus, burn wound necrosis can increase over time (termed burn wound progression or conversion) as release of inflammatory mediators and tissue edema (from the original burn injury as well as from resuscitation of the burn injury), or infection further compromises blood flow to already critically injured/ischemic tissues9. The zone of hyperemia, which surrounds the zone of stasis, comprises non-injured tissue with increased blood flow as a compensatory reaction to the burn8.
Burn wound infection control is critical because bacteria release various inflammatory substances such as endotoxins and oxygen free radicals that can increase burn wound conversion10. The zones of coagulation and stasis are the greatest sources of infection entry. Current infection control for burns involves maintenance of a moist healing environment, application of topical antimicrobials until spontaneous healing (for partial thickness burns), and/or early excision and wound coverage with split thickness skin grafts (STSG)(for full thickness or deep partial thickness burns)11,12. Burn wound conversion create a “moving target” situation in which the TBSA of necrotic tissue requiring excision and grafting can progressively increase in the first few days after thermal trauma13,14. On top of this, once the extent of burn requiring excision and closure is demarcated, the definitive treatment, autograft skin, is limited in supply—which further prolongs time to complete definitive wound closure. Thus, strategies to minimize burn wound progression/conversion (i.e., minimize tissue excision) and enhance wound closure success rates (i.e., maximize skin graft “take”) can accelerate recovery and decrease the morbidity and mortality of burn patients.
Disruption of the normal skin barrier in major burns alters immune function, producing an imbalance between pro- and anti-inflammatory cytokine syntheses and increasing susceptibility to post burn infection and sepsis8,15. Necrotic tissue and protein-rich wound exudates in burned tissue provide a rich growth medium promoting rapid bacterial colonization—even with modern topical antimicrobial use16,17. And due to poor blood flow to necrosis and stasis burn zones, systemic antibiotics do not decrease burn wound cellulitis or sepsis18,19.
Historically, burn wound infection has been the most common cause of mortality in thermally injured patients11. However, even with more modernized care of early wound excision/closure and topical antimicrobials, approximately 75% of all deaths in patients with severe burns over 40% TBSA are related to sepsis from burn wound infection or other infectious complications and/or inhalation injury18. Thus, while the overall incidence of burn wound infections has declined with implementation of early wound excision/closure; the data are inconclusive for large burns10,11. This underscores the need for better infection control in large burns.
The types of bacteria that colonize and infect burn patients and their antimicrobial susceptibilities are influenced by both the patient's body flora and the hospital environment flora20. But as a general guideline, resident gram-positive skin flora such as Streptococcus pyrogenes and Staphylococcus aureus (S. aureus) that reside within skin appendages initially colonize the wound in the first 24-48 hours11. By 48-72 hours, endogenous gram-negative organisms from respiratory or gastrointestinal sources such as Pseudomonas aeruginosa (P. aeruginosa), Klebsiella pneumoniae, and Escherichia coli (E. coli) begin populating the burn eschar and may predominate by day/In addition, US military personnel injured in Iraq or Afghanistan as well as burn patients in the US have found increased infection by multidrug-resistant Acinetobacter calcoaceticus-baumannii11. Meanwhile, delayed fungal infections (average 16 days from time of injury) (e.g., Candida species or Aspergillus species) can also occur and is regarded as an independent predictor of mortality21. From Table 1, S. aureus and coagulase negative Staphlococcus appear to be the most common gram-positive organism isolated, while
TABLE 1Common Organisms Identified in Burn WoundsStudy TimeFrame/SampleCollectionAverageTopicalTop 5 OrganismsSpecimenTimeCountry/% TBSATherapy−% PrevalenceMethodFrame# Patients(Range)UsedReferenceCoag neg Staph −44.3SwabsMay toTurkey22.9SilverErol et al.17S. Aureus −30.4fromNovember80(5-75%)sulphadiazineP. aeruginosa −12.5wound,2002Enterobacter spp. −2.6nares,Swab within 12Candida spp. −1.9axilla,hrs of injury,groin,7 d, 14 d, 21 dumbilicusPseudomonas spp. −36Swabs* June 1993 toIndiaN.S.AN.S.Revathi et al.22S. aureus −19fromJune 1997# patientsKlebsiella spp. −16woundsPatientnotProteus spp. −11collection timespecifiedE. faecalis −9frame notspecifiedMRSAB −40.7(I)C 45.6(II)N.S.June 1992 toKuwait46%SilverBang et al.18Acinetobacter −10.2(I) 15.5(II)May 1996943 (Group(10-90%; I)sulphadiazineMRSED −14.4(I) 2.9(II)(Group I)I)40%Pseudomonas −12.7(I) 2.9(II)June 1996 to939 (Group(2-95%; II)Mixed −12.7(I) 15.6(II)May 2000II)(Group II)S. Aureus 29(Bx)E 35(S)3 mm“2 year period”UKN.S.N.S.Steer et al.23Coag neg Staph 23(Bx) 21(S)punch orNo other74P. aeruginosa 17(Bx) 20(S)scalpel informationAcinetobacter 10(Bx) 11(S)ANDprovidedEnterobacter 9(Bx) 12(S)alginateswabAN.S.—not specifiedBMRSA—methicillin resistant S. aureusCI indicates Group I and “II” indicates Group II patientsDMRSE—methicillin-resistant S. epidermidis, a subgroup under coagulase-negative StaphylococcusE“Bx” indicates biopsy; “S” indicates swabPseudomonas and Acinetobacter are the most common gram-negative organisms. Thus, desirable infection control would require broad spectrum coverage against gram positive and negative organisms and ideally, fungi.
Presumptive diagnosis of an invasive bacterial infection is made when biopsied burn tissue contains >105 bacteria/gram tissue; however, the most reliable way to establish true tissue invasion is histological evidence of bacteria in viable tissue adjacent to or underneath the eschar (reviewed in5,12). With respect to the speed and morbidity associated with bacterial infection, Barret et al. performed quantitative bacteria cultures in 20 consecutive pediatric patients averaging 34±5 TBSA burns. Twelve of 20 patients had burn excision/closure within 24 hours of injury, while 8/20 had delayed excision/closure (7 d±2d). All patients were treated with silver sulfadiazine before surgery. Quantitative cultures revealed 104 bacteria/gram tissue in the burn eschar and 102 bacteria/gram tissue in the remaining post-excision wound bed for the acute excision group. In contrast, the delayed excision group exhibited up to 106 bacteria/gram tissue in the burn eschar and up to 104 bacteria/gram tissue in the remaining post-excision wound bed. The delayed group also demonstrated graft loss in 3 patients and sepsis in 2 patients after surgery16.
Standard tangential excision of burns requires removal of all “unhealthy” appearing tissue (e.g., brownish fat or bloodstained tissues) down to uniformly bright yellow fat and briskly bleeding vessels24. Barret et al.'s findings indicate that it is that it is practically impossible to “sterilize” colonized burn wound bed prior to grafting and that because of current limitations in topical antimicrobials at controlling infection, any significant delay in burn wound excision can significantly impact the degree of skin graft viability. Even more importantly, increased bacteria in delayed excision burn wounds may significantly increase the amount and depth of tissue that needs tangential excision. For a patient with a small 5% TBSA burn in the anterior mid thigh, delayed excision/wound infection may not represent a significant morbidity. However, for a 50% TBSA burn that involves bilateral lower and upper extremities, delayed excision/infection can have tremendous functional consequences if deep tissue excision to remove nonviable, bacteria invaded tissue results in significant exposure of tendons in the leg (e.g., Achilles, tibialis anterior) or in the hand (e.g., extrinsic extensors and flexors) and relatively avascular fascia over joints24. Moreover, fascial excision is also associated with increased extremity edema (due to reduced lymphatics), cutaneous denervation with possible sensation loss, and severe cosmetic deformity24. In addition, graft loss for a patient with limited donor sites can significantly prolong the time to wound closure—as the donor sites generally require ˜2 weeks before healing through re-epithelialization from epidermal appendages such as hair follicles, sebaceous glands, and sweat glands25. In addition, to avoid creating a non-healing full-thickness defect that itself would need to be grafted, each donor site can only be used a finite number of times since the dermis and the epithelial appendages in the dermis do not regenerate. Lastly, delayed wound closure, wound infection, and possibly even wound colonization can significantly increase the incidence of hypertrophic scarring—which can cause major negative long term functional and cosmetic sequelae26-31. Thus, controlling burn wound infection is critical to short term goals of minimizing septic complications, maximizing tissue salvage and wound closure success as well as long term goals of minimizing hypertrophic scarring/contractures and maximizing function.
Although early excision (within 24 hours) decreases bacteria colonization and improves wound closure outcomes 16, early excision may not be practical in patients that are not medically stable or in burns that are still converting (i.e., premature excision of all burned areas, including indeterminate 2nd degree burns, may result in tissue overexcision). This indicates that better infection control is critical for every day that definitive burn excision/closure therapy is delayed for medical or logistical reasons.
Because systemic antibiotics do not prevent burn wound cellulitis or sepsis11,18,19, topical antimicrobials and early wound debridement are first line defenses against invasive burn wound pathogens. The topical antimicrobial should form a protective bacteriostatic/bacteriocidal zone against deeper bacteria colonization or invasion. An ideal topical antimicrobial would exhibit the following: 1) good tissue penetration; 2) broad antimicrobial activity without encouraging drug resistance; 3) minimal local/systemic toxicity or side effects; 4) easy, infrequent application; 5) relatively pain free once applied. No current antimicrobial exhibits all the ideal properties and Table 2 summarizes the advantages/disadvantages of commonly used topical antimicrobials.
Historically, silver nitrate (AgNO3) was the first topical agent employed to delay burn eschar colonization in 1964 with the bactericidal component being cationic silver (Ag+)11,20. Initial use at a 10% solution was found to exhibit keratinocyte and fibroblast toxicity and current use is limited to 0.5% solutions11.
Disadvantages include total lack of eschar penetration, systemic effects (electrolyte imbalances), and adverse local effects (tissue staining)11,20,34. Although the exact bacteriostatic mechanism of mafenide is still not known35, it was developed at the US Army Surgical Research Unit (Fort Sam Houston, Tex.) and tested on humans in 196433. It is the only topical antimicrobial with significant eschar penetration due to mafenide's hydrophilic nature36. Disadvantages of MA cream include bacteriostatic rather than bactericidal activity, rapid tissue clearance (related to hydrophilic nature), metabolic acidosis11,20,34, and pain following application [due to the high osmolarity (2000 mOsm/kg) of the cream]37. The 5% MA solution was FDA approved as an orphan drug in 199833, exhibits similar antimicrobial and eschar penetration properties as the cream, but is significantly less painful due to lower osmolarity (340-500 mOsm/kg)35,37. To improve fungal coverage, 5% MA is often mixed with Nystatin powder (final 10,000 U/ml Nystatin)20,38. The limitations of silver nitrate and MA led to development of silver sulfadiazine (SSD) in 196833. SSD, a complex of sulfadiazine+silver nitrate with antimicrobial activity from the silver as well as the sulfonamide component, is the most commonly used topical burn antimicrobial20,39. Disadvantages of SSD include poor eschar
TABLE 2Commonly Used Burn Topical AntimicrobialsAgentAdvantagesDisadvantages0.5% Silver nitrateBactericidal against mostNo eschar penetrationsolutiongram positives, gramElectrolyte imbalance (hypotonic solution depletesIntroduced in 1964negatives and yeastwound cations)Avoids mucopurulentNeeds frequent applicationexudate formationDiscolors wound bed(pseudoeschar)Possible methmeglobinemiaMinimal pain afterRare silver toxicityapplicationNo hypersensitivityMafenide acetate -Bacteriostatic against mostPotential loss of bacteriostatic action at high (>106)historically 11.1% ingram positives, grambacterial loadswater-soluble cream,negatives; may be moreEffective concentration in eschar drops belowbut newereffective for clostridial andtherapeutic levels after 10 hours - needing twiceformulation is 8.5%pseudomonal infectionsdaily applicationFirst introduced inthan silver nitrate or SSDMetablic acidosis [drug and metabolite (p-1964Good eschar penetrationcarboxybenzenesulfonamide) inhibit carbonicanhydrase - can worsen ventilation]Pain after applicationPotential hypersensitivity1% SilverBactericidal against mostLess activity against certain gram negativessulfadiazine (SSD)gram positives and some(Enterobacter, Pseudomonas) and yeastwater soluble creamgram negativesPoor eschar penetrationDeveloped in 1968Minimal pain afterForms pseudoeschar that requires daily washingsapplicationNeutropeniaAPotential hypersensitivity to sulfa componentRare silver toxicityMafenide acetate -(Similar to cream)(Similar to cream)5% solutionLess pain after applicationEffective concentration in eschar drops belowFirst introduced invs. creamtherapeutic levels after 6-8 hours - needing 3x-4x1971daily applicationActicoatBactericidal against mostPoor eschar penetrationRayon/polyestergram positives, gramRequires maintenance of moist dressings for silvercore encased innegatives and fungusreleasedense polyethyleneSustained silver release forRare silver toxicitymesh coated with3-7 dnanocrystallineMinimizes pain from dailysilver.dressingsTable information modified and compiled from the following references: Cioffi et al.12, D'Avignon et al.11, Tredget et al.20, Martineau and Davis32, Barillo33ANeutropenia thought to be due to transient depression of granulocyte-macrophage progenitor cells in the marrow11.penetration, less effective gram negative activity, and neutropenia20,34. Acticoat is a novel nanocrystalline silver complex with broad antimicrobial properties that also releases silver cations20. Disadvantages also include poor eschar penetration20.
It is clear that burn wound sepsis is still common despite topical antimicrobial use11. The early vs. late excision wound colonization data from Barret et al.16 reinforces the finding that current antimicrobials do not provide a protective buffer zone that effectively controls colonization/invasion of viable subeschar tissue. Treatment failures can occur under several scenarios: 1) bacterial penetration into the eschar exceeds the penetration capacity of commonly used antimicrobials such as SSD, Acticoat, or silver nitrate; 2) effective bacteriostatic/bacteriocidal tissue drug levels cannot be maintained despite initial drug penetration by MA-based topicals; and 3) true bacterial drug resistance to topical agents. True bacterial resistance in this context means that the same bacteria, when taken out of an in vivo wound environment without protective matrices or biofilms, will continue to exhibit drug resistance in vitro. Fortunately, true bacterial resistance for certain silver based antimicrobials is rare40 and bacteriostatic resistance to MA relatively uncommon41.
With respect to silver, it's action as an antiseptic may contribute to the rarer incidence of bacterial resistance40. Antiseptics are short-acting, broad spectrum agents that non-selectively target cellular activities in both human and bacterial cells—and as such, cannot be given systemically due to excessive toxicity. Antiseptics are less likely to promote bacterial resistance because of their relatively rapid and broad anti-cellular activities42. In contrast, antibiotics bind specific bacteria chemical targets that do not exist in humans, and are thus less cytotoxic to human cells than bacterial cells. However, antibiotic binding specificity, while desirably limiting toxicity, also narrows the bacterial species and strain susceptibility to a given antibiotic—and contributes significantly to antibiotic resistance42. The current prevalence of multi-antibiotic resistant organisms has renewed interest in the use of the antiseptic silver as an effective, but relatively less toxic antimicrobial42.
The antimicrobial properties of silver have long been recognized. It has been used for centuries in water recycling and sanitization and for treatment of wound infections43,44. In 1884, a German obstetrician introduced silver nitrate application to newborn eyes to prevent gonorrheal infection44. In the early 20th century surgeon, William S. Halstead, used silver foil as wound dressings44. With the development of modern antibiotics, silver use for infection control declined significantly; however, beginning the late 1960s, silver experienced wide use in cutaneous wounds, most notably, as evident in the preceding paragraphs, in burn care43. Modern silver use includes silver based dressings in the form of creams, foams, hydrogels, hydrocolloids, polymeric films, and meshes43. In addition, silver is used to reduce bacterial colonization/infection in a broad range of devices such as vascular and urinary catheters43, endotracheal tubes, and implantable prostheses46. However, it is difficult to directly extrapolate published literature on silver toxicity to this present study. This is because different forms of silver reservoir (e.g. silver salts such as AgNO3, silver compounds such as silver sulfadiazine, or nanocrystalline silver) have different profiles of silver release and bioactivity47. Even within one reservoir category of nanocrystalline silver, there is tremendous variation in particle size, particle aggregation, concentration or coating thickness (in implants), rate of release from implants or surfaces, and the solution used when studying release rates. From the extensive skin literature on silver use, general agreement exists that silver can be toxic to keratinocytes in vitro47, but in vivo studies disagree on whether actual keratinocyte reepithelialization is decreased48 or increased49. Moreover, Tian et al. showed more rapid healing and less scar after addition of silver nanoparticles in mouse wounds50. Thus, in vitro studies may overestimate in vivo cytotoxicity51.
Both silver nitrate and nanosilver materials achieve their antimicrobial activity by generation and/or release of cationic silver (Ag+) [i.e., ionic silver Ag (1)]; however, they may differ in the reservoir form for the active silver ions42. For instance, the reservoir form for AgNO3 is a chemical combination of silver and nitrate, while the reservoir form for Acticoat are silver nanoparticles (AgNANO). Non-nanoscale elemental silver [Ag (0)] used in silverware and jewelry is relatively insoluble in most fluids, and hence there is minimal oxidative Ag+ release42. In contrast, because nanoscale particles have relatively large surface to mass ratio, they exhibit much more solubility and chemical reactivity, and hence much higher oxidative Ag+ release and/or much higher formation of partially oxidized silver nanoparticles with chemisorbed (surface bound) Ag+52. In general, silver nanoparticles<50 nm are believed to exhibit more satisfacgtory antimicrobial activity52,53.
Mechanistically, Ag+ is thought to attach to specific thiol groups containing sulfur and hydrogen found in a variety of structural and functional bacterial proteins42. Because of this, Ag+ can bind and disrupt multiple components of bacterial structure/metabolism including: cell wall components, cellular transport and enzyme systems such as the respiratory cytochromes, DNA and RNA processes to prevent cell division and transcription43. Bacterial resistance to silver, although described and some of the genetic basis elucidated44, may be less likely than resistance to antibiotics as bacterial survival would require at least three separate mutations in three different bacterial systems—all within one generation of bacteria43.
Overall, nanoscale silver is believed to be a more effective antimicrobial than silver nitrate because: 1) the solution rate of active Ag+ from AgNANO is greater than the inactivation rate of Ag+ by serum proteins, making it possible to achieve higher and more sustained mean inhibitory concentrations (MIC)54 (i.e., better Ag+ reservoir) and 2) increased bactericidal activity deriving from released Ag+ as well as AgNANO particles53 exhibiting chemisorbed surface Ag+52. In support of this, in vitro time kill-kinetic assays demonstrated good antimicrobial activity for Acticoat against fungal subspecies (e.g., Candida albicans or glabrata as well as Mucor and Aspergillus), while silver nitrate and SSD demonstrated activity for only C. albicans40. These results indicate that silver bactericidal activity can vary depending on the form of silver used and that current nanosilver formulations can exhibit significant broad antimicrobial activity. However, variable release rates depending on dressing hydration55 and inadequate tissue penetration are still significant issues.
With respect to MA, although it is bacteriostatic, its ability to penetrate rapidly into tissues and relatively low incidence of documented resistance can be important for short term treatment of open wounds. Using zone of inhibition assays, Kucan et al. found that 5% MA was effective against all 43 different A. baumannii strains collected from service members injured in Irag and Afghanistan56. Kucan et al. also cited no evidence of resistance in over 11,000 strains of P. aeruginosa collected over 25 years at the US Army Institute of Surgical Research56. Using a similar type inhibition zone assay, Gallant-Behm et al. also found good 5% MA activity against S. aureus, MRSA, and most gram negatives including P. aeruginosa, but no activity against vancomycin resistant Enterococcus (VRE), Burkholderia cepacia, E. coli, or any fungal species40. These results indicate that the significant benefits associated with increased MA penetration are somewhat offset by its limited antimicrobial spectrum.
Mafentide tissue permeability studies were originally performed by Harrison et al. who analyzed absorption of 14C-labeled MA through burned rat and human skin57. The high water solubility and low plasma protein affinity of 11.2% MA cream permits rapid burned tissue penetration with a peak concentration of 1 mg/100 g tissue within 30 minutes. However, rapid tissue penetration of MA is also associated with relatively rapid tissue clearance—and relatively rapid drop in effectively bacteriostatic local tissues concentrations. Thus, strategies to enhance mafenide retention in burn wounds may increase the antimicrobial effectiveness of MA as well as potentially decrease the total dose (with respect to concentration and application frequency) and thus minimize systemic toxicity (e.g., metabolic acidosis). Taken as a whole, these observations indicate that adequate tissue penetration, adequate tissue delivery (i.e., ability to maintain sustained tissue drug levels), and microorganism susceptibility are critical to maximizing antimicrobial activity.
Timely debridement of all devitalized tissue is critical to infection control in both burns and other injuries. For cases where the wound bed is well vascularized and the TBSA needing coverage does not exceed the amount of autograft skin available, STSG can be applied and the wound closed in one stage. However, for burn cases with insufficient autograft donor skin, other forms of permanent or temporary wound coverage are required.
For permanent wound coverage, the only alternative to conventional meshed autograft skin are cultured epithelial autografts (CEA). CEA use however is hampered by tremendous costs, need for 3 week culture period, long term fragility manifesting as recurrent open wounds, and increased rate of burn scar contractures requiring more reconstructive procedures58.
For temporary coverage, allograft skin, xenograft skin, or Integra-DRT (Integra LifeSciences Inc., Plainsboro, N.J.) can be applied. Allograft advantages are its ability to be revascularized by the recipient wound bed, resulting in increased graft adherence and better infection control39. Disadvantages are need for reapplication every 2 weeks due to rejection and possible disease transmission. In addition, because initial allograft skin (as well as autograft) survival depends on imbibition (net diffusion of plasma into graft), followed by inosculation (growth of recipient endothelial cells into pre-existing donor capillary tubes)59,60, allograft cannot be placed over areas with significant (>1 cm2) non-vascularized tissue (e.g., bone devoid of periosteum, tendon devoid of paratenon, open joints)61. Porcine dermal xenografts are further disadvantaged by less adherence and protection from desiccation and infection than allograft due to lack of revascularization by the recipient wound bed resulting in degenerative necrosis and need for frequent reapplication39.
Integra-DRT is a bilayer membrane in which the inner, dermal replacement layer is made of a porous matrix of cross-linked bovine tendon collagen fibers and a glycosaminoglycan (chondroitin-6-sulfate) that is manufactured with a controlled porosity and defined degradation rate; the outer layer is a polysiloxane polymer that functions as a temporary epidermis24,62. Integra-DRT is acellular and nonviable when grafted but is incorporated and vascularized by viable tissue underneath and adjacent the Integra-DRT61. Once incorporated, a thin epidermal autograft (0.004-0.006 inches) can then be grafted over Integra-DRT for definitive closure. Integra-DRT advantages include ability to induce tissue ingrowth over poorly-vascularized, but viable, wound bed areas (e.g., exposed bone, tendon, joint)61. Disadvantages include need for two-step surgery process before final wound closure, increased infection rates, and prolonged times for adequate ingrowth/angiogenesis into Integra-DRT. Cited infection rates ranged from 0 to 55% from multiple Integra sponsored trials in the Product Information Sheet. This rate is consistent with other published reports in the literature ranging from about 0-30% despite application of topical antimicrobials61,63-65. With respect to tissue incorporation, the Product Information Sheet recommends 14-21 days before epidermal autograft placement.
It has been observed that the 1.5-2 mm thick Integra-DRT66 is usually vascularized in 2 to 3 weeks when relying on direct vertical ingrowth from the recipient wound bed. But in cases where Integra-DRT is grafted over non- or poorly vascularized structures, incorporation is dependent on initial vertical ingrowth (in areas where Integra-DRT is in contact with vascularized wound bed) and then horizontal or radial ingrowth through the Integra-DRT (in areas where Integra-DRT is in contact with a non vascularized wound bed). Depending on the total area of non-vascularized wound bed, incorporation can take as long as 6-8 weeks61. Interestingly, use of a negative pressure wound therapy device (vacuum-assisted closure device-VAC; KCl Inc., San Antonio, Tex.) over Integra-DRT appears to both reduce the incidence of infection (range 0-12.5%)63-65 and time to definitive autograft wound closure (mean time to grafting was 10 days by Jeschke et al.64 and 7.25 days by Molnr et al.65 This suggests that interventions promoting tissue ingrowth can decrease the time to Integra-DRT incorporation and possibly decrease the incidence of Integra-DRT infection. However, burn patients may not have enough intact, non-injured skin for VAC application.
It is clear that current burn wound coverage is still largely dependent on autograft skin. Requirement for successful autograft survival include low wound bioburden and good recipient bed vascularization59. Thus strategies to promote infection control and tissue ingrowth may help autograft mediated wound closure success rates—especially in wound beds with large bioburdens even after adequate resection (i.e., as discussed in Barret et al. noted autograft loss in 3 out of 8 patients in the delayed excision group with high wound bioburden16). In addition, promoting infection control and tissue ingrowth may also reduce infection rates during Integra-DRT incorporation as well as allow for faster skin grafting over Integra-DRT—thereby decreasing the overall wound closure time. Lastly, decreased autograft or Integra treatment failures can reduce the need for reoperation, resulting in significant time and cost savings. Thus, therapies that promote fibroblast migration and vascular ingrowth with concomitant antimicrobial activity are required to increase the efficacy and efficiency of present skin closure methods.
The embodiments of the present invention address these concerns as well as others that are apparent by one having ordinary skill in the art.